Molecular mechanisms of cadherin function during cortical migration

During development of the cerebral cortex, different types of neurons migrate from distinct origins to create the different cortical layers and settle within them. Along their way, migrating neurons use cell adhesion molecules on their surface to interact with other cells that will play critical roles to ensure that migration is successful. Radially migrating projection neurons interact primarily with radial glia and Cajal-Retzius cells, whereas interneurons originating in the subpallium follow a longer, tangential route and encounter additional cellular substrates before reaching the cortex. Cell-cell adhesion is therefore essential for the correct migration of cortical neurons. Several members of the cadherin superfamily of cell adhesion proteins, which mediate cellular interactions through calcium-dependent, mostly homophilic binding, have been shown to play important roles during neuronal migration of both projection neurons and interneurons. Although several classical cadherins and protocadherins are involved in this process, the most prominent is CDH2. This mini review will explore the cellular and molecular mechanisms underpinning cadherin function during cortical migration, including recent advances in our understanding of the control of adhesive strength through regulation of cadherin surface levels. Keywords: cerebral cortex, neuron, migration, cell surface, adhesion molecules, CDH2, molecular mechanis

Transcriptional control of embryonic and adult neural progenitor activity

Neural precursors generate neurons in the embryonic brain and in restricted niches of the adult brain in a process called neurogenesis. The precise control of cell proliferation and differentiation in time and space required for neurogenesis depends on sophisticated orchestration of gene transcription in neural precursor cells. Much progress has been made in understanding the transcriptional regulation of neurogenesis, which relies on dose- and context-dependent expression of specific transcription factors that regulate the maintenance and proliferation of neural progenitors, followed by their differentiation into lineage-specified cells. Here, we review some of the most widely studied neurogenic transcription factors in the embryonic cortex and neurogenic niches in the adult brain. We compare functions of these transcription factors in embryonic and adult neurogenesis, highlighting biochemical, developmental, and cell biological properties. Our goal is to present an overview of transcriptional regulation underlying neurogenesis in the developing cerebral cortex and in the adult brain

Transcriptional control of embryonic and adult neural progenitor activity

Neural precursors generate neurons in the embryonic brain and in restricted niches of the adult brain in a process called neurogenesis. The precise control of cell proliferation and differentiation in time and space required for neurogenesis depends on sophisticated orchestration of gene transcription in neural precursor cells. Much progress has been made in understanding the transcriptional regulation of neurogenesis, which relies on dose- and context-dependent expression of specific transcription factors that regulate the maintenance and proliferation of neural progenitors, followed by their differentiation into lineage-specified cells. Here, we review some of the most widely studied neurogenic transcription factors in the embryonic cortex and neurogenic niches in the adult brain. We compare functions of these transcription factors in embryonic and adult neurogenesis, highlighting biochemical, developmental, and cell biological properties. Our goal is to present an overview of transcriptional regulation underlying neurogenesis in the developing cerebral cortex and in the adult brain

The neuronal migration hypothesis of dyslexia : a critical evaluation 30 years on

This work was supported by the Wellcome Trust (092071/Z/10/Z to A.P.M., Z.M. and A.V.-B., and 082498/Z/07/Z to D.V.M.B.); L.G.G. receive a Doctoral Training Award from the Medical Research Council; S.P. is a Royal Society University Research Fellow.The capacity for language is one of the key features underlying the complexity of human cognition and its evolution. However, little is known about the neurobiological mechanisms that mediate normal or impaired linguistic ability. For developmental dyslexia, early postmortem studies conducted in the 1980s linked the disorder to subtle defects in the migration of neurons in the developing neocortex. These early studies were reinforced by human genetic analyses that identified dyslexia susceptibility genes and subsequent evidence of their involvement in neuronal migration. In this review, we examine recent experimental evidence that does not support the link between dyslexia and neuronal migration. We critically evaluate gene function studies conducted in rodent models and draw attention to the lack of robust evidence from histopathological and imaging studies in humans. Our review suggests that the neuronal migration hypothesis of dyslexia should be reconsidered, and the neurobiological basis of dyslexia should be approached with a fresh start.PreprintPublisher PDFPeer reviewe

The placenta protects the fetal circulation from anxiety-driven elevations in maternal serum levels of brain-derived neurotrophic factor.

Brain-derived neurotrophic factor (BDNF) plays crucial roles in brain function. Numerous studies report alterations in BDNF levels in human serum in various neurological conditions, including mood disorders such as depression. However, little is known about BDNF levels in the blood during pregnancy. We asked whether maternal depression and/or anxiety during pregnancy were associated with altered serum BDNF levels in mothers (n = 251) and their new-born infants (n = 212). As prenatal exposure to maternal mood disorders significantly increases the risk of neurological conditions in later life, we also examined the possibility of placental BDNF transfer by developing a new mouse model. We found no association between maternal symptoms of depression and either maternal or infant cord blood serum BDNF. However, maternal symptoms of anxiety correlated with significantly raised maternal serum BDNF exclusively in mothers of boys (r = 0.281; P = 0.005; n = 99). Serum BDNF was significantly lower in male infants than female infants but neither correlated with maternal anxiety symptoms. Consistent with this observation, we found no evidence for BDNF transfer across the placenta. We conclude that the placenta protects the developing fetus from maternal changes in serum BDNF that could otherwise have adverse consequences for fetal development

Neuregulin-4 is required for maintaining soma size of pyramidal neurons in the motor cortex

The regulation of neuronal soma size is essential for appropriate brain circuit function and its dysregulation is associated with several neurodevelopmental disorders. A defect in the dendritic growth and elaboration of motor neocortical pyramidal neurons in neonates lacking neuregulin-4 (NRG4) has previously been reported. In this study, we investigated if the loss of NRG4 causes further morphological defects that are specific to these neurons. We analysed the soma size of pyramidal neurons of layers 2/3 and 5 of the motor cortex and a subpopulation of multipolar interneurons in this neocortical region in Nrg4+/+ and Nrg4-/- mice. There were significant decreases in pyramidal neuron soma size in Nrg4-/- mice compared with Nrg4+/+ littermates at all stages studied (P10, P30 and P60). The reduction was especially marked at P10 and in layer 5 pyramidal neurons. Soma size was not significantly different for multipolar interneurons at any age. This in vivo phenotype was replicated in pyramidal neurons cultured from Nrg4-/- mice and was rescued by neuregulin-4 treatment. Analysis of a public single-cell RNA sequencing repository revealed discrete Nrg4 and Erbb4 expression in subpopulations of layer 5 pyramidal neurons, suggesting that the observed defects were due in part to loss of autocrine Nrg4/ErbB4 signalling. The pyramidal phenotype in the motor cortex of Nrg4-/- mice was associated with a lack of Rotarod test improvement in P60 mice, suggesting that absence of NRG4 causes alterations in motor performance

Dbx1-derived pyramidal neurons are generated locally in the developing murine neocortex

The neocortex generates at the dorsal region of the pallium in the forebrain. Several adjacent structures also contribute with neurons to neocortex. Ventral pallium is considered to generate several populations of neurons that arrive through tangential migration to the neocortex. Amongst them are the Cajal-Retzius cells and some transient pyramidal neurons. However, the specific site and timing of generation, trajectory of migration and actual contribution to the pyramidal population remains elusive. Here we investigate the spatio-temporal origin of neuronal populations from ventral pallium in an in vivo model, using a transposase mediated in utero electroporation method in embryonic mouse in vivo. From E11 to E14 cells born at the lateral corner of the neocortical neuroepithelium including the ventral pallium migrated ventro-laterally to settle all areas of the ventral telencephalon. Specifically, neurons migrated into amygdala, olfactory cortices and claustrum. However, we found no evidence for any neurons migrating tangentially towards the neocortex, regardless the antero-posterior level and developmental time of the electroporation. Our results challenge the described ventral-pallial origin of the transient pyramidal neuron population. In order to find the exact origin of cortical neurons that were previously Dbx1-fate mapped we used the promoter region of the murine Dbx1 locus to selectively target Dbx1-expressing progenitors and label their lineage. We found these progenitors in low numbers in all pallial areas, and not only in the ventral pallial ventricular zone. Our findings on the local cortical origin of the Dbx1-expressing pyramidal neurons reconcile the observation of Dbx1 expressing neurons in the cortex without evidence of dorsal tangential migration from ventral pallium and provide a new framework for the origin of the transient Dbx1-derived pyramidal neuron population. We conclude that these neurons are born locally within the dorsal pallial neuroepithelium

Cellular and behavioral characterization of Pcdh19 mutant mice: subtle molecular changes, increased exploratory behavior and an impact of social environment

Mutations in the X-linked cell adhesion protein PCDH19 lead to seizures, cognitive impairment, and other behavioral comorbidities when present in a mosaic pattern. Neither the molecular mechanisms underpinning this disorder nor the function of PCDH19 itself are well understood. By combining RNA in situ hybridization with immunohistochemistry and analyzing single-cell RNA sequencing datasets, we reveal Pcdh19 expression in cortical interneurons and provide a first account of the subtypes of neurons expressing Pcdh19/PCDH19, both in the mouse and the human cortex. Our quantitative analysis of the Pcdh19 mutant mouse exposes subtle changes in cortical layer composition, with no major alterations of the main axonal tracts. In addition, Pcdh19 mutant animals, particularly females, display preweaning behavioral changes, including reduced anxiety and increased exploratory behavior. Importantly, our experiments also reveal an effect of the social environment on the behavior of wild-type littermates of Pcdh19 mutant mice, which show alterations when compared with wild-type animals not housed with mutants

Proteomic analysis of the developing mammalian brain links PCDH19 to the Wnt/β-catenin signalling pathway

Clustering Epilepsy (CE) is a neurological disorder caused by pathogenic variants of the Protocadherin 19 (PCDH19) gene. PCDH19 encodes a protein involved in cell adhesion and Estrogen Receptor α mediated-gene regulation. To gain further insights into the molecular role of PCDH19 in the brain, we investigated the PCDH19 interactome in the developing mouse hippocampus and cortex. Combined with a meta-analysis of all reported PCDH19 interacting proteins, our results show that PCDH19 interacts with proteins involved in actin, microtubule, and gene regulation. We report CAPZA1, αN-catenin and, importantly, β-catenin as novel PCDH19 interacting proteins. Furthermore, we show that PCDH19 is a regulator of β-catenin transcriptional activity, and that this pathway is disrupted in CE individuals. Overall, our results support the involvement of PCDH19 in the cytoskeletal network and point to signalling pathways where PCDH19 plays critical roles